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Low-risk TAVR loses ground at 2 years in PARTNER 3
Transcatheter aortic valve replacement (TAVR) continued to show superiority over surgical replacement in terms of the primary composite endpoint in low-surgical-risk patients at 2 years of follow-up in the landmark randomized PARTNER 3 trial, but the between-group differences favoring the transcatheter procedure in some key outcomes have narrowed considerably, Michael J. Mack, MD, reported in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“On the basis of 1-year data, many physicians were counseling patients that TAVR outcomes were better than surgery. Now we see that the outcomes are roughly the same at 2 years,” said Dr. Mack, who is medical director of cardiothoracic surgery and chairman of the Baylor Scott & White The Heart Hospital – Plano (Tex.) Research Center.
PARTNER 3 randomized 1,000 patients with severe symptomatic aortic stenosis with a tricuspid valve and a very low mean Society of Thoracic Surgeons risk score of 1.9% to TAVR with the Sapien 3 valve or surgical aortic valve replacement (SAVR). The 1-year results presented at ACC 2019 caused a huge stir, with the primary composite outcome of death, stroke, or cardiovascular rehospitalization occurring in 8.5% of TAVR patients and 15.6% of the SAVR group, representing a 48% relative risk reduction and a resounding win for TAVR (N Engl J Med. 2019 May 2;380:1695-705). At 2 years, the difference in the composite outcome remained statistically significant, but the gap had closed: 11.5% with TAVR and 17.4% with SAVR for a 37% relative risk reduction.
Moreover, the between-group difference in stroke, which at 1 year was significantly in favor of TAVR at 1.2% versus 3.3%, was no longer significant at 2 years, with rates of 2.4% versus 3.6%. Nor was the difference in mortality significant: 2.4% with TAVR, 3.2% with SAVR.
What was a statistically significant between-group difference at 2 years – and an eye-catching one at that – involved the cumulative incidence of valve thrombosis confirmed by CT or echocardiography: 2.6% in the TAVR arm, compared with 0.7% with SAVR, with most of these unwanted events coming in year 2.
The good news was there was no echocardiographic evidence of deterioration in valve structure or function in either study arm at 2 years. The mean gradients and aortic valve areas remained unchanged in both arms between 1 and 2 years, as did the frequency of mild or moderate paravalvular leak. Prospective follow-up will continue annually out to 10 years.
“I think it’s way too early to expect to see a signal, but I think it’s somewhat comforting at this point that there’s no signal of early structural valve deterioration,” Dr. Mack said.
Discussant Howard C. Hermann, MD, commented: “I guess the biggest concern in looking at the data is the increase in stroke and valve thrombosis, both numerically and relative to SAVR, between years 1 and 2.”
Dr. Mack offered a note of reassurance regarding the valve thrombosis findings: The rates he presented were based upon the now-outdated second Valve Academic Research Consortium (VARC-2) definition, per study protocol. When he and his coinvestigators recalculated the valve thrombosis rates using the contemporary VARC-3 definition of valve deterioration and bioprosthetic valve failure, the incidence was very low and not significantly different in the two study arms, at roughly 1%.
Dr. Hermann, professor of medicine and director of the cardiac catheterization laboratories at the University of Pennsylvania, Philadelphia, had a question: As a clinician taking care of TAVR patients, what clinical or hemodynamic findings should prompt an imaging study looking for valve thrombus or deterioration that might prompt initiating oral anticoagulation?
“If there’s a change in hemodynamics, an increasing valve gradient, if there’s increasing paravalvular leak, or if there’s a change in symptoms, that should prompt an imaging study. Only with confirmation of valve thrombosis on an imaging study should anticoagulation be considered. Oral anticoagulation is not benign: Of the six clinical events associated with valve thrombosis in the study, two were related to anticoagulation,” Dr. Mack replied.
“Regarding whether patients should receive warfarin or a novel anticoagulant, I don’t think we have evidence that there’s benefit to anything other than warfarin at the current time,” he added.
Dr. Mack reported receiving research support from Edwards Lifesciences, the sponsor of PARTNER 3, as well as from Abbott, Gore, and Medtronic.
Transcatheter aortic valve replacement (TAVR) continued to show superiority over surgical replacement in terms of the primary composite endpoint in low-surgical-risk patients at 2 years of follow-up in the landmark randomized PARTNER 3 trial, but the between-group differences favoring the transcatheter procedure in some key outcomes have narrowed considerably, Michael J. Mack, MD, reported in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“On the basis of 1-year data, many physicians were counseling patients that TAVR outcomes were better than surgery. Now we see that the outcomes are roughly the same at 2 years,” said Dr. Mack, who is medical director of cardiothoracic surgery and chairman of the Baylor Scott & White The Heart Hospital – Plano (Tex.) Research Center.
PARTNER 3 randomized 1,000 patients with severe symptomatic aortic stenosis with a tricuspid valve and a very low mean Society of Thoracic Surgeons risk score of 1.9% to TAVR with the Sapien 3 valve or surgical aortic valve replacement (SAVR). The 1-year results presented at ACC 2019 caused a huge stir, with the primary composite outcome of death, stroke, or cardiovascular rehospitalization occurring in 8.5% of TAVR patients and 15.6% of the SAVR group, representing a 48% relative risk reduction and a resounding win for TAVR (N Engl J Med. 2019 May 2;380:1695-705). At 2 years, the difference in the composite outcome remained statistically significant, but the gap had closed: 11.5% with TAVR and 17.4% with SAVR for a 37% relative risk reduction.
Moreover, the between-group difference in stroke, which at 1 year was significantly in favor of TAVR at 1.2% versus 3.3%, was no longer significant at 2 years, with rates of 2.4% versus 3.6%. Nor was the difference in mortality significant: 2.4% with TAVR, 3.2% with SAVR.
What was a statistically significant between-group difference at 2 years – and an eye-catching one at that – involved the cumulative incidence of valve thrombosis confirmed by CT or echocardiography: 2.6% in the TAVR arm, compared with 0.7% with SAVR, with most of these unwanted events coming in year 2.
The good news was there was no echocardiographic evidence of deterioration in valve structure or function in either study arm at 2 years. The mean gradients and aortic valve areas remained unchanged in both arms between 1 and 2 years, as did the frequency of mild or moderate paravalvular leak. Prospective follow-up will continue annually out to 10 years.
“I think it’s way too early to expect to see a signal, but I think it’s somewhat comforting at this point that there’s no signal of early structural valve deterioration,” Dr. Mack said.
Discussant Howard C. Hermann, MD, commented: “I guess the biggest concern in looking at the data is the increase in stroke and valve thrombosis, both numerically and relative to SAVR, between years 1 and 2.”
Dr. Mack offered a note of reassurance regarding the valve thrombosis findings: The rates he presented were based upon the now-outdated second Valve Academic Research Consortium (VARC-2) definition, per study protocol. When he and his coinvestigators recalculated the valve thrombosis rates using the contemporary VARC-3 definition of valve deterioration and bioprosthetic valve failure, the incidence was very low and not significantly different in the two study arms, at roughly 1%.
Dr. Hermann, professor of medicine and director of the cardiac catheterization laboratories at the University of Pennsylvania, Philadelphia, had a question: As a clinician taking care of TAVR patients, what clinical or hemodynamic findings should prompt an imaging study looking for valve thrombus or deterioration that might prompt initiating oral anticoagulation?
“If there’s a change in hemodynamics, an increasing valve gradient, if there’s increasing paravalvular leak, or if there’s a change in symptoms, that should prompt an imaging study. Only with confirmation of valve thrombosis on an imaging study should anticoagulation be considered. Oral anticoagulation is not benign: Of the six clinical events associated with valve thrombosis in the study, two were related to anticoagulation,” Dr. Mack replied.
“Regarding whether patients should receive warfarin or a novel anticoagulant, I don’t think we have evidence that there’s benefit to anything other than warfarin at the current time,” he added.
Dr. Mack reported receiving research support from Edwards Lifesciences, the sponsor of PARTNER 3, as well as from Abbott, Gore, and Medtronic.
Transcatheter aortic valve replacement (TAVR) continued to show superiority over surgical replacement in terms of the primary composite endpoint in low-surgical-risk patients at 2 years of follow-up in the landmark randomized PARTNER 3 trial, but the between-group differences favoring the transcatheter procedure in some key outcomes have narrowed considerably, Michael J. Mack, MD, reported in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“On the basis of 1-year data, many physicians were counseling patients that TAVR outcomes were better than surgery. Now we see that the outcomes are roughly the same at 2 years,” said Dr. Mack, who is medical director of cardiothoracic surgery and chairman of the Baylor Scott & White The Heart Hospital – Plano (Tex.) Research Center.
PARTNER 3 randomized 1,000 patients with severe symptomatic aortic stenosis with a tricuspid valve and a very low mean Society of Thoracic Surgeons risk score of 1.9% to TAVR with the Sapien 3 valve or surgical aortic valve replacement (SAVR). The 1-year results presented at ACC 2019 caused a huge stir, with the primary composite outcome of death, stroke, or cardiovascular rehospitalization occurring in 8.5% of TAVR patients and 15.6% of the SAVR group, representing a 48% relative risk reduction and a resounding win for TAVR (N Engl J Med. 2019 May 2;380:1695-705). At 2 years, the difference in the composite outcome remained statistically significant, but the gap had closed: 11.5% with TAVR and 17.4% with SAVR for a 37% relative risk reduction.
Moreover, the between-group difference in stroke, which at 1 year was significantly in favor of TAVR at 1.2% versus 3.3%, was no longer significant at 2 years, with rates of 2.4% versus 3.6%. Nor was the difference in mortality significant: 2.4% with TAVR, 3.2% with SAVR.
What was a statistically significant between-group difference at 2 years – and an eye-catching one at that – involved the cumulative incidence of valve thrombosis confirmed by CT or echocardiography: 2.6% in the TAVR arm, compared with 0.7% with SAVR, with most of these unwanted events coming in year 2.
The good news was there was no echocardiographic evidence of deterioration in valve structure or function in either study arm at 2 years. The mean gradients and aortic valve areas remained unchanged in both arms between 1 and 2 years, as did the frequency of mild or moderate paravalvular leak. Prospective follow-up will continue annually out to 10 years.
“I think it’s way too early to expect to see a signal, but I think it’s somewhat comforting at this point that there’s no signal of early structural valve deterioration,” Dr. Mack said.
Discussant Howard C. Hermann, MD, commented: “I guess the biggest concern in looking at the data is the increase in stroke and valve thrombosis, both numerically and relative to SAVR, between years 1 and 2.”
Dr. Mack offered a note of reassurance regarding the valve thrombosis findings: The rates he presented were based upon the now-outdated second Valve Academic Research Consortium (VARC-2) definition, per study protocol. When he and his coinvestigators recalculated the valve thrombosis rates using the contemporary VARC-3 definition of valve deterioration and bioprosthetic valve failure, the incidence was very low and not significantly different in the two study arms, at roughly 1%.
Dr. Hermann, professor of medicine and director of the cardiac catheterization laboratories at the University of Pennsylvania, Philadelphia, had a question: As a clinician taking care of TAVR patients, what clinical or hemodynamic findings should prompt an imaging study looking for valve thrombus or deterioration that might prompt initiating oral anticoagulation?
“If there’s a change in hemodynamics, an increasing valve gradient, if there’s increasing paravalvular leak, or if there’s a change in symptoms, that should prompt an imaging study. Only with confirmation of valve thrombosis on an imaging study should anticoagulation be considered. Oral anticoagulation is not benign: Of the six clinical events associated with valve thrombosis in the study, two were related to anticoagulation,” Dr. Mack replied.
“Regarding whether patients should receive warfarin or a novel anticoagulant, I don’t think we have evidence that there’s benefit to anything other than warfarin at the current time,” he added.
Dr. Mack reported receiving research support from Edwards Lifesciences, the sponsor of PARTNER 3, as well as from Abbott, Gore, and Medtronic.
FROM ACC 2020
When the going gets tough, ophthalmologists call the rheumatologist
MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.
Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.
“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.
Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.
However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.
“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.
He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.
Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.
Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.
“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.
Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.
Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.
“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.
The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.
“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.
Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).
It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
Get to know teprotumumab
Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.
“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”
In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.
“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.
Obtaining payer approval
“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.
“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.
Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.
MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.
Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.
“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.
Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.
However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.
“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.
He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.
Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.
Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.
“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.
Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.
Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.
“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.
The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.
“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.
Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).
It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
Get to know teprotumumab
Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.
“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”
In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.
“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.
Obtaining payer approval
“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.
“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.
Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.
MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.
Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.
“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.
Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.
However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.
“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.
He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.
Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.
Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.
“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.
Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.
Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.
“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.
The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.
“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.
Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).
It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
Get to know teprotumumab
Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.
“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”
In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.
“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.
Obtaining payer approval
“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.
“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.
Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.
REPORTING FROM RWCS 2020
When to suspect calciphylaxis and what to do about it
If the shoe fits a presumptive clinical diagnosis of calciphylaxis, wear it – and don’t assume that ordering imaging studies or histology will make for a better fit or is even necessary.
That was the key message of Karl M. Saardi, MD, during his video presentation at a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.
“ said Dr. Saardi, a dermatology resident at Georgetown University in Washington, D.C.
He presented a single-center, retrospective study that underscored the diagnostic challenges posed by calciphylaxis, a condition for which there are no generally accepted clinical, radiographic, or histologic diagnostic criteria.
The rare skin condition is characterized by calcium deposition in small arterioles and capillaries in the skin and subcutaneous tissue. It’s most common in patients with end-stage renal disease who are on dialysis; however, there is also an increasingly recognized nonuremic variant that’s associated with the use of warfarin, chronic steroids, obesity, and possibly with being antiphospholipid antibody positive.
Calciphylaxis is an extremely painful condition – the pain is ischemic in nature – and it’s associated with substantial morbidity as well as a mortality rate that in many series exceeds 50%. Affected individuals typically present with progressive, painful retiform purpura on the legs, belly, buttocks, and other fatty body sites.
Dr. Saardi’s study entailed a retrospective look at the medical records and pathologic reports of 57 patients who underwent skin biopsy for suspected calciphylaxis. Of the 57, 18 had no antecedent imaging studies done during the preceding 3 months; 8 of those 18 (40%), had a confirmatory positive biopsy. A total of 39 patients did have imaging studies, deemed positive for calciphylaxis in 11 cases, which in only 5 of the 11 imaging-positive cases (45%) were subsequently confirmed by positive biopsy.
And finally, of the 28 patients with negative imaging studies, 10 (36%), had a positive biopsy. Those positive biopsy rates, ranging from 36% to 45%, did not differ statistically. Thus, whether an imaging study was positive or negative, or wasn’t even done, made no difference in terms of the ultimate diagnosis.
“You may not need imaging studies, because imaging has often been done before the consultation is requested because people are looking for things like arterial thrombus, cellulitis, [deep vein thrombosis] or something like that,” Dr. Saardi noted. “In our series, the indication was never calciphylaxis, it was always something like pain, infection, swelling, suspected [deep vein thrombosis], things like that.”
The classic signature of calciphylaxis on plain x-ray is net-like calcifications in skin and subcutaneous tissue. In one study, this often-subtle finding was associated with a 830% increased likelihood of a positive biopsy, with a specificity of 90%; however, these x-ray changes were only found in 13 of 29 patients with biopsy-confirmed calciphylaxis.
“It’s really important when you request plain films in these patients to review the images yourself or together with the radiologist because oftentimes the indication for imaging will be very different from what we’re looking for. Radiologists often won’t know to look for this specifically,” Dr. Saardi said.
The classic histopathologic finding is calcification of the small- and medium-sized vessels in the dermis and subcutaneous soft tissue. However, sometimes all that’s present are small intravascular inflammatory thrombi with intimal hyperplasia.
Skin biopsies are not infrequently falsely negative or nondiagnostic. To maximize the utility of the procedure, it’s important to go deep and gather a tissue sample that extends into subcutaneous tissue.
“You need to do a very deep punch or double-punch biopsy,” he said. “Another key is to avoid biopsy if the pretest probability of calciphylaxis is high because a negative biopsy shouldn’t necessarily reassure you or cause you to withhold treatment. And with the concern about pathergy or Koebnerization of the area causing a wound that’s never going to heal, sometimes a biopsy is not needed if the pretest suspicion is high enough.”
Other investigators have shown that the likelihood of an informative biopsy is enhanced by using a calcium stain on the specimen and having an experienced dermatopathologist do the evaluation. Also, the use of a radiographically guided core needle biopsy to ensure that the physician is getting sufficiently deep into subcutaneous fat is now under evaluation.
In addition to plain radiographs, other imaging methods that are sometimes used to evaluate soft-tissue sites for suspected calciphylaxis included CT and ultrasound. Dr. Saardi is particularly intrigued by reports from investigators at Harvard University regarding the utility of nuclear bone scintigraphy; in one study, this form of imaging was positive in 16 of 18 patients with clinically diagnosed calciphylaxis, versus just 1 of 31 controls with end-stage renal disease.
“We’ve started doing this in situations where biopsy is not desirable or feasible at that moment,” he said.
Dr. Saardi reported having no financial conflicts regarding his presentation.
If the shoe fits a presumptive clinical diagnosis of calciphylaxis, wear it – and don’t assume that ordering imaging studies or histology will make for a better fit or is even necessary.
That was the key message of Karl M. Saardi, MD, during his video presentation at a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.
“ said Dr. Saardi, a dermatology resident at Georgetown University in Washington, D.C.
He presented a single-center, retrospective study that underscored the diagnostic challenges posed by calciphylaxis, a condition for which there are no generally accepted clinical, radiographic, or histologic diagnostic criteria.
The rare skin condition is characterized by calcium deposition in small arterioles and capillaries in the skin and subcutaneous tissue. It’s most common in patients with end-stage renal disease who are on dialysis; however, there is also an increasingly recognized nonuremic variant that’s associated with the use of warfarin, chronic steroids, obesity, and possibly with being antiphospholipid antibody positive.
Calciphylaxis is an extremely painful condition – the pain is ischemic in nature – and it’s associated with substantial morbidity as well as a mortality rate that in many series exceeds 50%. Affected individuals typically present with progressive, painful retiform purpura on the legs, belly, buttocks, and other fatty body sites.
Dr. Saardi’s study entailed a retrospective look at the medical records and pathologic reports of 57 patients who underwent skin biopsy for suspected calciphylaxis. Of the 57, 18 had no antecedent imaging studies done during the preceding 3 months; 8 of those 18 (40%), had a confirmatory positive biopsy. A total of 39 patients did have imaging studies, deemed positive for calciphylaxis in 11 cases, which in only 5 of the 11 imaging-positive cases (45%) were subsequently confirmed by positive biopsy.
And finally, of the 28 patients with negative imaging studies, 10 (36%), had a positive biopsy. Those positive biopsy rates, ranging from 36% to 45%, did not differ statistically. Thus, whether an imaging study was positive or negative, or wasn’t even done, made no difference in terms of the ultimate diagnosis.
“You may not need imaging studies, because imaging has often been done before the consultation is requested because people are looking for things like arterial thrombus, cellulitis, [deep vein thrombosis] or something like that,” Dr. Saardi noted. “In our series, the indication was never calciphylaxis, it was always something like pain, infection, swelling, suspected [deep vein thrombosis], things like that.”
The classic signature of calciphylaxis on plain x-ray is net-like calcifications in skin and subcutaneous tissue. In one study, this often-subtle finding was associated with a 830% increased likelihood of a positive biopsy, with a specificity of 90%; however, these x-ray changes were only found in 13 of 29 patients with biopsy-confirmed calciphylaxis.
“It’s really important when you request plain films in these patients to review the images yourself or together with the radiologist because oftentimes the indication for imaging will be very different from what we’re looking for. Radiologists often won’t know to look for this specifically,” Dr. Saardi said.
The classic histopathologic finding is calcification of the small- and medium-sized vessels in the dermis and subcutaneous soft tissue. However, sometimes all that’s present are small intravascular inflammatory thrombi with intimal hyperplasia.
Skin biopsies are not infrequently falsely negative or nondiagnostic. To maximize the utility of the procedure, it’s important to go deep and gather a tissue sample that extends into subcutaneous tissue.
“You need to do a very deep punch or double-punch biopsy,” he said. “Another key is to avoid biopsy if the pretest probability of calciphylaxis is high because a negative biopsy shouldn’t necessarily reassure you or cause you to withhold treatment. And with the concern about pathergy or Koebnerization of the area causing a wound that’s never going to heal, sometimes a biopsy is not needed if the pretest suspicion is high enough.”
Other investigators have shown that the likelihood of an informative biopsy is enhanced by using a calcium stain on the specimen and having an experienced dermatopathologist do the evaluation. Also, the use of a radiographically guided core needle biopsy to ensure that the physician is getting sufficiently deep into subcutaneous fat is now under evaluation.
In addition to plain radiographs, other imaging methods that are sometimes used to evaluate soft-tissue sites for suspected calciphylaxis included CT and ultrasound. Dr. Saardi is particularly intrigued by reports from investigators at Harvard University regarding the utility of nuclear bone scintigraphy; in one study, this form of imaging was positive in 16 of 18 patients with clinically diagnosed calciphylaxis, versus just 1 of 31 controls with end-stage renal disease.
“We’ve started doing this in situations where biopsy is not desirable or feasible at that moment,” he said.
Dr. Saardi reported having no financial conflicts regarding his presentation.
If the shoe fits a presumptive clinical diagnosis of calciphylaxis, wear it – and don’t assume that ordering imaging studies or histology will make for a better fit or is even necessary.
That was the key message of Karl M. Saardi, MD, during his video presentation at a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.
“ said Dr. Saardi, a dermatology resident at Georgetown University in Washington, D.C.
He presented a single-center, retrospective study that underscored the diagnostic challenges posed by calciphylaxis, a condition for which there are no generally accepted clinical, radiographic, or histologic diagnostic criteria.
The rare skin condition is characterized by calcium deposition in small arterioles and capillaries in the skin and subcutaneous tissue. It’s most common in patients with end-stage renal disease who are on dialysis; however, there is also an increasingly recognized nonuremic variant that’s associated with the use of warfarin, chronic steroids, obesity, and possibly with being antiphospholipid antibody positive.
Calciphylaxis is an extremely painful condition – the pain is ischemic in nature – and it’s associated with substantial morbidity as well as a mortality rate that in many series exceeds 50%. Affected individuals typically present with progressive, painful retiform purpura on the legs, belly, buttocks, and other fatty body sites.
Dr. Saardi’s study entailed a retrospective look at the medical records and pathologic reports of 57 patients who underwent skin biopsy for suspected calciphylaxis. Of the 57, 18 had no antecedent imaging studies done during the preceding 3 months; 8 of those 18 (40%), had a confirmatory positive biopsy. A total of 39 patients did have imaging studies, deemed positive for calciphylaxis in 11 cases, which in only 5 of the 11 imaging-positive cases (45%) were subsequently confirmed by positive biopsy.
And finally, of the 28 patients with negative imaging studies, 10 (36%), had a positive biopsy. Those positive biopsy rates, ranging from 36% to 45%, did not differ statistically. Thus, whether an imaging study was positive or negative, or wasn’t even done, made no difference in terms of the ultimate diagnosis.
“You may not need imaging studies, because imaging has often been done before the consultation is requested because people are looking for things like arterial thrombus, cellulitis, [deep vein thrombosis] or something like that,” Dr. Saardi noted. “In our series, the indication was never calciphylaxis, it was always something like pain, infection, swelling, suspected [deep vein thrombosis], things like that.”
The classic signature of calciphylaxis on plain x-ray is net-like calcifications in skin and subcutaneous tissue. In one study, this often-subtle finding was associated with a 830% increased likelihood of a positive biopsy, with a specificity of 90%; however, these x-ray changes were only found in 13 of 29 patients with biopsy-confirmed calciphylaxis.
“It’s really important when you request plain films in these patients to review the images yourself or together with the radiologist because oftentimes the indication for imaging will be very different from what we’re looking for. Radiologists often won’t know to look for this specifically,” Dr. Saardi said.
The classic histopathologic finding is calcification of the small- and medium-sized vessels in the dermis and subcutaneous soft tissue. However, sometimes all that’s present are small intravascular inflammatory thrombi with intimal hyperplasia.
Skin biopsies are not infrequently falsely negative or nondiagnostic. To maximize the utility of the procedure, it’s important to go deep and gather a tissue sample that extends into subcutaneous tissue.
“You need to do a very deep punch or double-punch biopsy,” he said. “Another key is to avoid biopsy if the pretest probability of calciphylaxis is high because a negative biopsy shouldn’t necessarily reassure you or cause you to withhold treatment. And with the concern about pathergy or Koebnerization of the area causing a wound that’s never going to heal, sometimes a biopsy is not needed if the pretest suspicion is high enough.”
Other investigators have shown that the likelihood of an informative biopsy is enhanced by using a calcium stain on the specimen and having an experienced dermatopathologist do the evaluation. Also, the use of a radiographically guided core needle biopsy to ensure that the physician is getting sufficiently deep into subcutaneous fat is now under evaluation.
In addition to plain radiographs, other imaging methods that are sometimes used to evaluate soft-tissue sites for suspected calciphylaxis included CT and ultrasound. Dr. Saardi is particularly intrigued by reports from investigators at Harvard University regarding the utility of nuclear bone scintigraphy; in one study, this form of imaging was positive in 16 of 18 patients with clinically diagnosed calciphylaxis, versus just 1 of 31 controls with end-stage renal disease.
“We’ve started doing this in situations where biopsy is not desirable or feasible at that moment,” he said.
Dr. Saardi reported having no financial conflicts regarding his presentation.
National Watchman registry reports impressive procedural safety
Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.
“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.
The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.
Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.
“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”
Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.
The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.
The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.
By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.
Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.
He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.
“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.
Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?
Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.
Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).
In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.
The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).
Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.
SOURCE: Freeman JF. ACC 2020, Abstract 409-10.
Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.
“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.
The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.
Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.
“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”
Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.
The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.
The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.
By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.
Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.
He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.
“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.
Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?
Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.
Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).
In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.
The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).
Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.
SOURCE: Freeman JF. ACC 2020, Abstract 409-10.
Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.
“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.
The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.
Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.
“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”
Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.
The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.
The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.
By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.
Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.
He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.
“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.
Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?
Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.
Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).
In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.
The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).
Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.
SOURCE: Freeman JF. ACC 2020, Abstract 409-10.
FROM ACC 2020
Belimumab may improve skin in scleroderma
MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.
At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.
This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.
For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.
The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.
Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.
The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.
“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.
Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.
Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.
For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.
When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.
The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.
She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.
“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.
She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.
MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.
At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.
This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.
For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.
The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.
Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.
The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.
“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.
Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.
Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.
For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.
When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.
The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.
She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.
“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.
She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.
MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.
At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.
This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.
For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.
The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.
Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.
The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.
“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.
Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.
Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.
For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.
When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.
The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.
She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.
“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.
She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.
REPORTING FROM RWCS 2020
Novel acne drug now under review at the FDA
LAHAINA, HAWAII – by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.
“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.
“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.
The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.
The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.
Dr. Sprague reported having no financial conflicts regarding her presentation.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.
“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.
“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.
The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.
The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.
Dr. Sprague reported having no financial conflicts regarding her presentation.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.
“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.
“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.
The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.
The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.
Dr. Sprague reported having no financial conflicts regarding her presentation.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM THE SDEF HAWAII DERMATOLOGY SEMINAR
Routinely screen for depression in atopic dermatitis
Jonathan I. Silverberg, MD, PhD, declared in a video presentation during a virtual meeting held by the George Washington University department of dermatology.
The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.
Dr. Silverberg presented highlights of his recent study of depression screening rates in the National Ambulatory Medical Care Survey, an annual population-based survey by the National Center for Health Statistics. He and his coinvestigator analyzed 9,345 office visits for atopic dermatitis (AD) and 2,085 for psoriasis (Br J Dermatol. 2019 Oct 24. doi: 10.1111/bjd.18629.). The picture that emerged showed that there is much room for improvement.
“We found that depression screening rates were abysmally low in atopic dermatitis patients, with less than 2% patients being screened. There was very little difference in screening rates between patients on an advanced therapy, like systemic phototherapy or a biologic, compared to those who were just on topical therapy alone, meaning even the more severe patients aren’t being asked these questions. And no difference between dermatologists and primary care physicians,” said Dr. Silverberg, director of clinical research and contact dermatitis in the department of dermatology at George Washington University, Washington.
For Dr. Silverberg, known for his pioneering work documenting the marked yet often-underappreciated negative impact of AD on quality of life and mental health, these rock-bottom screening rates were particularly galling.
“There are very high rates of anxiety and depression amongst our patients with atopic dermatitis,” the dermatologist emphasized. “Mental health symptoms are an incredibly important domain in atopic dermatitis that we need to ask our patients about. We don’t ask enough.
“This to me is actually a very important symptom to measure. It’s not just a theoretical construct involved in understanding the burden of the disease, it’s something that’s actionable because most of these cases of mental health symptoms are reversible or modifiable with improved control of the atopic dermatitis,” he continued. “I use this as an indication to step up therapy. If a patient is clinically depressed and we believe that’s secondary to their chronic atopic dermatitis, this is a reason to step up therapy to something stronger.”
If the depressive symptoms don’t improve after stepping up the intensity of the dermatologic therapy, it’s probably time for the patient to see a mental health professional, Dr. Silverberg advised, adding, “I’m not telling every dermatology resident out there to become a psychiatrist.”
Depression and anxiety in AD: How common?
In an analysis of multiyear data from the Medical Expenditure Panel Surveys, an annual population-based project conducted by the Agency for Healthcare Research and Quality, Dr. Silverberg and a coinvestigator found that adults with AD were an adjusted 186% more likely than those without AD to screen positive for depressive symptoms on the two-item Patient Health Questionnaire (PHQ-2), with rates of 44.3% and 21.9%, respectively. The AD patients were also 500% more likely to screen positive for severe psychological distress, with a 25.9% rate of having a Kessler-6 index score of 13 or more, compared with 5.5% in adults without AD.
The rate of severe psychological distress was higher in adults with AD than in those with asthma, diabetes, hypertension, urticaria, or psoriasis, and was comparable with the rate in individuals with autoimmune disease (Ann Allergy Asthma Immunol. 2019 Aug;123[2]:179-85).
“It’s surprising when you think that the majority of the cases of atopic dermatitis in the population are mild and yet when you look at a population-based sample such as this you see a strong signal come up. It means that, with all the dilution of mild disease, the signal is still there. It emphasizes that even patients with mild disease get these depressive symptoms and psychosocial distress,” Dr. Silverberg observed.
In a separate analysis of the same national database, this time looking at Short Form-6D health utility scores – a measure of overall quality of life encompassing key domains including vitality, physical function, mental health, fatigue – adults with AD scored markedly worse than individuals with no chronic health disorders. Health utility scores were particularly low in adults with AD and comorbid symptoms of anxiety or depression, suggesting that those affective symptoms are major drivers of the demonstrably poor quality of life in adult AD (Ann Allergy Asthma Immunol. 2020 Jan;124[1]:88-9).
In the Atopic Dermatitis in America Study, Dr. Silverberg and coinvestigators cross-sectionally surveyed 2,893 adults using the seven-item Hospital Anxiety and Depression Scale anxiety (HADS-A) and depression (HADS-D) assessment instruments. Individuals with AD as determined using the modified U.K. Diagnostic Criteria had dramatically higher rates of both depression and anxiety. For example, the prevalence of a HADS-A score of 11 or more, which is considered to be case finding for clinically important anxiety, was 28.6% in adults with AD, nearly twice the 15.5% prevalence in those without the dermatologic disease. A HADS-D score of 11 or greater was present in 13.5% of subjects with AD and 9% of those without.
HADS-A and -D scores were higher in adults with moderate AD, compared with mild disease, and higher still in those with severe AD. Indeed, virtually all individuals with moderate to severe AD had symptoms of anxiety and depression, which in a large proportion had gone undiagnosed. A multivariate analysis strongly suggested that AD severity was the major driver of anxiety and depression in adults with AD (Br J Dermatol. 2019 Sep;181[3]:554-65).
An important finding was that 100% of adults with AD who had scores in the severe range on three validated measures of itch, frequency of symptoms, and lesion severity had borderline or abnormal scores on the HADS-A and -D.
“Of course, if you don’t ask, you’re not going to know about it,” Dr. Silverberg noted.
Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.
Jonathan I. Silverberg, MD, PhD, declared in a video presentation during a virtual meeting held by the George Washington University department of dermatology.
The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.
Dr. Silverberg presented highlights of his recent study of depression screening rates in the National Ambulatory Medical Care Survey, an annual population-based survey by the National Center for Health Statistics. He and his coinvestigator analyzed 9,345 office visits for atopic dermatitis (AD) and 2,085 for psoriasis (Br J Dermatol. 2019 Oct 24. doi: 10.1111/bjd.18629.). The picture that emerged showed that there is much room for improvement.
“We found that depression screening rates were abysmally low in atopic dermatitis patients, with less than 2% patients being screened. There was very little difference in screening rates between patients on an advanced therapy, like systemic phototherapy or a biologic, compared to those who were just on topical therapy alone, meaning even the more severe patients aren’t being asked these questions. And no difference between dermatologists and primary care physicians,” said Dr. Silverberg, director of clinical research and contact dermatitis in the department of dermatology at George Washington University, Washington.
For Dr. Silverberg, known for his pioneering work documenting the marked yet often-underappreciated negative impact of AD on quality of life and mental health, these rock-bottom screening rates were particularly galling.
“There are very high rates of anxiety and depression amongst our patients with atopic dermatitis,” the dermatologist emphasized. “Mental health symptoms are an incredibly important domain in atopic dermatitis that we need to ask our patients about. We don’t ask enough.
“This to me is actually a very important symptom to measure. It’s not just a theoretical construct involved in understanding the burden of the disease, it’s something that’s actionable because most of these cases of mental health symptoms are reversible or modifiable with improved control of the atopic dermatitis,” he continued. “I use this as an indication to step up therapy. If a patient is clinically depressed and we believe that’s secondary to their chronic atopic dermatitis, this is a reason to step up therapy to something stronger.”
If the depressive symptoms don’t improve after stepping up the intensity of the dermatologic therapy, it’s probably time for the patient to see a mental health professional, Dr. Silverberg advised, adding, “I’m not telling every dermatology resident out there to become a psychiatrist.”
Depression and anxiety in AD: How common?
In an analysis of multiyear data from the Medical Expenditure Panel Surveys, an annual population-based project conducted by the Agency for Healthcare Research and Quality, Dr. Silverberg and a coinvestigator found that adults with AD were an adjusted 186% more likely than those without AD to screen positive for depressive symptoms on the two-item Patient Health Questionnaire (PHQ-2), with rates of 44.3% and 21.9%, respectively. The AD patients were also 500% more likely to screen positive for severe psychological distress, with a 25.9% rate of having a Kessler-6 index score of 13 or more, compared with 5.5% in adults without AD.
The rate of severe psychological distress was higher in adults with AD than in those with asthma, diabetes, hypertension, urticaria, or psoriasis, and was comparable with the rate in individuals with autoimmune disease (Ann Allergy Asthma Immunol. 2019 Aug;123[2]:179-85).
“It’s surprising when you think that the majority of the cases of atopic dermatitis in the population are mild and yet when you look at a population-based sample such as this you see a strong signal come up. It means that, with all the dilution of mild disease, the signal is still there. It emphasizes that even patients with mild disease get these depressive symptoms and psychosocial distress,” Dr. Silverberg observed.
In a separate analysis of the same national database, this time looking at Short Form-6D health utility scores – a measure of overall quality of life encompassing key domains including vitality, physical function, mental health, fatigue – adults with AD scored markedly worse than individuals with no chronic health disorders. Health utility scores were particularly low in adults with AD and comorbid symptoms of anxiety or depression, suggesting that those affective symptoms are major drivers of the demonstrably poor quality of life in adult AD (Ann Allergy Asthma Immunol. 2020 Jan;124[1]:88-9).
In the Atopic Dermatitis in America Study, Dr. Silverberg and coinvestigators cross-sectionally surveyed 2,893 adults using the seven-item Hospital Anxiety and Depression Scale anxiety (HADS-A) and depression (HADS-D) assessment instruments. Individuals with AD as determined using the modified U.K. Diagnostic Criteria had dramatically higher rates of both depression and anxiety. For example, the prevalence of a HADS-A score of 11 or more, which is considered to be case finding for clinically important anxiety, was 28.6% in adults with AD, nearly twice the 15.5% prevalence in those without the dermatologic disease. A HADS-D score of 11 or greater was present in 13.5% of subjects with AD and 9% of those without.
HADS-A and -D scores were higher in adults with moderate AD, compared with mild disease, and higher still in those with severe AD. Indeed, virtually all individuals with moderate to severe AD had symptoms of anxiety and depression, which in a large proportion had gone undiagnosed. A multivariate analysis strongly suggested that AD severity was the major driver of anxiety and depression in adults with AD (Br J Dermatol. 2019 Sep;181[3]:554-65).
An important finding was that 100% of adults with AD who had scores in the severe range on three validated measures of itch, frequency of symptoms, and lesion severity had borderline or abnormal scores on the HADS-A and -D.
“Of course, if you don’t ask, you’re not going to know about it,” Dr. Silverberg noted.
Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.
Jonathan I. Silverberg, MD, PhD, declared in a video presentation during a virtual meeting held by the George Washington University department of dermatology.
The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic.
Dr. Silverberg presented highlights of his recent study of depression screening rates in the National Ambulatory Medical Care Survey, an annual population-based survey by the National Center for Health Statistics. He and his coinvestigator analyzed 9,345 office visits for atopic dermatitis (AD) and 2,085 for psoriasis (Br J Dermatol. 2019 Oct 24. doi: 10.1111/bjd.18629.). The picture that emerged showed that there is much room for improvement.
“We found that depression screening rates were abysmally low in atopic dermatitis patients, with less than 2% patients being screened. There was very little difference in screening rates between patients on an advanced therapy, like systemic phototherapy or a biologic, compared to those who were just on topical therapy alone, meaning even the more severe patients aren’t being asked these questions. And no difference between dermatologists and primary care physicians,” said Dr. Silverberg, director of clinical research and contact dermatitis in the department of dermatology at George Washington University, Washington.
For Dr. Silverberg, known for his pioneering work documenting the marked yet often-underappreciated negative impact of AD on quality of life and mental health, these rock-bottom screening rates were particularly galling.
“There are very high rates of anxiety and depression amongst our patients with atopic dermatitis,” the dermatologist emphasized. “Mental health symptoms are an incredibly important domain in atopic dermatitis that we need to ask our patients about. We don’t ask enough.
“This to me is actually a very important symptom to measure. It’s not just a theoretical construct involved in understanding the burden of the disease, it’s something that’s actionable because most of these cases of mental health symptoms are reversible or modifiable with improved control of the atopic dermatitis,” he continued. “I use this as an indication to step up therapy. If a patient is clinically depressed and we believe that’s secondary to their chronic atopic dermatitis, this is a reason to step up therapy to something stronger.”
If the depressive symptoms don’t improve after stepping up the intensity of the dermatologic therapy, it’s probably time for the patient to see a mental health professional, Dr. Silverberg advised, adding, “I’m not telling every dermatology resident out there to become a psychiatrist.”
Depression and anxiety in AD: How common?
In an analysis of multiyear data from the Medical Expenditure Panel Surveys, an annual population-based project conducted by the Agency for Healthcare Research and Quality, Dr. Silverberg and a coinvestigator found that adults with AD were an adjusted 186% more likely than those without AD to screen positive for depressive symptoms on the two-item Patient Health Questionnaire (PHQ-2), with rates of 44.3% and 21.9%, respectively. The AD patients were also 500% more likely to screen positive for severe psychological distress, with a 25.9% rate of having a Kessler-6 index score of 13 or more, compared with 5.5% in adults without AD.
The rate of severe psychological distress was higher in adults with AD than in those with asthma, diabetes, hypertension, urticaria, or psoriasis, and was comparable with the rate in individuals with autoimmune disease (Ann Allergy Asthma Immunol. 2019 Aug;123[2]:179-85).
“It’s surprising when you think that the majority of the cases of atopic dermatitis in the population are mild and yet when you look at a population-based sample such as this you see a strong signal come up. It means that, with all the dilution of mild disease, the signal is still there. It emphasizes that even patients with mild disease get these depressive symptoms and psychosocial distress,” Dr. Silverberg observed.
In a separate analysis of the same national database, this time looking at Short Form-6D health utility scores – a measure of overall quality of life encompassing key domains including vitality, physical function, mental health, fatigue – adults with AD scored markedly worse than individuals with no chronic health disorders. Health utility scores were particularly low in adults with AD and comorbid symptoms of anxiety or depression, suggesting that those affective symptoms are major drivers of the demonstrably poor quality of life in adult AD (Ann Allergy Asthma Immunol. 2020 Jan;124[1]:88-9).
In the Atopic Dermatitis in America Study, Dr. Silverberg and coinvestigators cross-sectionally surveyed 2,893 adults using the seven-item Hospital Anxiety and Depression Scale anxiety (HADS-A) and depression (HADS-D) assessment instruments. Individuals with AD as determined using the modified U.K. Diagnostic Criteria had dramatically higher rates of both depression and anxiety. For example, the prevalence of a HADS-A score of 11 or more, which is considered to be case finding for clinically important anxiety, was 28.6% in adults with AD, nearly twice the 15.5% prevalence in those without the dermatologic disease. A HADS-D score of 11 or greater was present in 13.5% of subjects with AD and 9% of those without.
HADS-A and -D scores were higher in adults with moderate AD, compared with mild disease, and higher still in those with severe AD. Indeed, virtually all individuals with moderate to severe AD had symptoms of anxiety and depression, which in a large proportion had gone undiagnosed. A multivariate analysis strongly suggested that AD severity was the major driver of anxiety and depression in adults with AD (Br J Dermatol. 2019 Sep;181[3]:554-65).
An important finding was that 100% of adults with AD who had scores in the severe range on three validated measures of itch, frequency of symptoms, and lesion severity had borderline or abnormal scores on the HADS-A and -D.
“Of course, if you don’t ask, you’re not going to know about it,” Dr. Silverberg noted.
Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.
Alirocumab effective in homozygous FH
Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We’re not getting most patients to goal, but we’re certainly getting them closer to goal. A lot of patients will still need further therapies that don’t rely on up-regulation of the LDL receptor, such as lipoprotein apheresis,” observed Dr. Blom, head of the division of lipidology at the University of Cape Town (South Africa).
Of the patients on alirocumab, 57%had at least a 30% reduction in LDL at 12 weeks, and 27% had a 50% reduction or more.
Alirocumab had salutary effects on other atherogenic lipids: roughly a 20% reduction from baseline in lipoprotein (a), a 23% decrease in apolipoprotein B, and a 25% reduction in non-HDL cholesterol.
Dr. Blom noted that, as is also the case for statins in HoFH, the LDL response to alirocumab in patients with this genetically complex disorder is more variable and generally weaker than in other hypercholesterolemic populations.
“We saw some patients getting up to 60%-70% LDL reduction in alirocumab, but a lot of patients getting much less,” he said.
Alirocumab was well tolerated in adults with HoFH, with the same favorable safety profile that’s been established in other patient populations.
Discussant Raul Santos, MD, commented that the ODYSSEY HoFH results are quite similar to those reported in patients with HoFH in an earlier study of evolocumab (Repatha), another PCSK9 inhibitor. The magnitude of LDL-lowering achieved with these biologic agents is such that, were treatment to start early in life, patients with HoFH might expect to experience an extra 10-15 years of life free of cardiovascular events.
“Certainly PCSK9 inhibitors should be the next step after statins and ezetimibe. They’re much less expensive and more available than apheresis,” said Dr. Santos, director of the lipid clinic at the Heart Institute of the University of São Paulo.
Since many patients with this rare disorder experience their first cardiovascular event in adolescence or young adulthood, Dr. Santos said, it’s very important to expand PCSK9 inhibitor therapy to the pediatric HoFH population. Two studies are ongoing in childlren.
The ODYSSEY HoFH trial was funded by Regeneron and Sanofi. Dr. Blom reported serving as a paid consultant to Sanofi, Akcea, Amgen, and Gemphire.
Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We’re not getting most patients to goal, but we’re certainly getting them closer to goal. A lot of patients will still need further therapies that don’t rely on up-regulation of the LDL receptor, such as lipoprotein apheresis,” observed Dr. Blom, head of the division of lipidology at the University of Cape Town (South Africa).
Of the patients on alirocumab, 57%had at least a 30% reduction in LDL at 12 weeks, and 27% had a 50% reduction or more.
Alirocumab had salutary effects on other atherogenic lipids: roughly a 20% reduction from baseline in lipoprotein (a), a 23% decrease in apolipoprotein B, and a 25% reduction in non-HDL cholesterol.
Dr. Blom noted that, as is also the case for statins in HoFH, the LDL response to alirocumab in patients with this genetically complex disorder is more variable and generally weaker than in other hypercholesterolemic populations.
“We saw some patients getting up to 60%-70% LDL reduction in alirocumab, but a lot of patients getting much less,” he said.
Alirocumab was well tolerated in adults with HoFH, with the same favorable safety profile that’s been established in other patient populations.
Discussant Raul Santos, MD, commented that the ODYSSEY HoFH results are quite similar to those reported in patients with HoFH in an earlier study of evolocumab (Repatha), another PCSK9 inhibitor. The magnitude of LDL-lowering achieved with these biologic agents is such that, were treatment to start early in life, patients with HoFH might expect to experience an extra 10-15 years of life free of cardiovascular events.
“Certainly PCSK9 inhibitors should be the next step after statins and ezetimibe. They’re much less expensive and more available than apheresis,” said Dr. Santos, director of the lipid clinic at the Heart Institute of the University of São Paulo.
Since many patients with this rare disorder experience their first cardiovascular event in adolescence or young adulthood, Dr. Santos said, it’s very important to expand PCSK9 inhibitor therapy to the pediatric HoFH population. Two studies are ongoing in childlren.
The ODYSSEY HoFH trial was funded by Regeneron and Sanofi. Dr. Blom reported serving as a paid consultant to Sanofi, Akcea, Amgen, and Gemphire.
Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We’re not getting most patients to goal, but we’re certainly getting them closer to goal. A lot of patients will still need further therapies that don’t rely on up-regulation of the LDL receptor, such as lipoprotein apheresis,” observed Dr. Blom, head of the division of lipidology at the University of Cape Town (South Africa).
Of the patients on alirocumab, 57%had at least a 30% reduction in LDL at 12 weeks, and 27% had a 50% reduction or more.
Alirocumab had salutary effects on other atherogenic lipids: roughly a 20% reduction from baseline in lipoprotein (a), a 23% decrease in apolipoprotein B, and a 25% reduction in non-HDL cholesterol.
Dr. Blom noted that, as is also the case for statins in HoFH, the LDL response to alirocumab in patients with this genetically complex disorder is more variable and generally weaker than in other hypercholesterolemic populations.
“We saw some patients getting up to 60%-70% LDL reduction in alirocumab, but a lot of patients getting much less,” he said.
Alirocumab was well tolerated in adults with HoFH, with the same favorable safety profile that’s been established in other patient populations.
Discussant Raul Santos, MD, commented that the ODYSSEY HoFH results are quite similar to those reported in patients with HoFH in an earlier study of evolocumab (Repatha), another PCSK9 inhibitor. The magnitude of LDL-lowering achieved with these biologic agents is such that, were treatment to start early in life, patients with HoFH might expect to experience an extra 10-15 years of life free of cardiovascular events.
“Certainly PCSK9 inhibitors should be the next step after statins and ezetimibe. They’re much less expensive and more available than apheresis,” said Dr. Santos, director of the lipid clinic at the Heart Institute of the University of São Paulo.
Since many patients with this rare disorder experience their first cardiovascular event in adolescence or young adulthood, Dr. Santos said, it’s very important to expand PCSK9 inhibitor therapy to the pediatric HoFH population. Two studies are ongoing in childlren.
The ODYSSEY HoFH trial was funded by Regeneron and Sanofi. Dr. Blom reported serving as a paid consultant to Sanofi, Akcea, Amgen, and Gemphire.
REPORTING FROM ACC 2020
Renal denervation shown safe and effective in pivotal trial
Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We saw clinically meaningful blood pressure reductions at 3 months,” reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.
That’s encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.
The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.
The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls. Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7–mm Hg reduction in 24-hour DBP, compared with a 0.8–mm Hg decrease in controls.
Office SBP – the secondary endpoint – decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.
These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1-2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons. Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.
A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.
The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.
A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%-9% nonetheless tested positive at the second test.
That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: “I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it’s fascinating that some of the people that you asked not to take the medications were taking them.”
While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance. At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don’t need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn’t undergo RDN.
Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.
“Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was,” he explained.
Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7–mm Hg reduction in 24-hour SBP “reasonably impressive – that’s actually a pretty good number for an antihypertensive clinical trial.” He was also favorably impressed by RDN’s safety in a 44-site study.
“The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications,” commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.
Simultaneous with Dr. Boehm’s presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).
The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.
SOURCE: Boehm M. ACC 2020, Abstract 406-15.
Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We saw clinically meaningful blood pressure reductions at 3 months,” reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.
That’s encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.
The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.
The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls. Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7–mm Hg reduction in 24-hour DBP, compared with a 0.8–mm Hg decrease in controls.
Office SBP – the secondary endpoint – decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.
These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1-2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons. Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.
A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.
The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.
A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%-9% nonetheless tested positive at the second test.
That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: “I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it’s fascinating that some of the people that you asked not to take the medications were taking them.”
While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance. At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don’t need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn’t undergo RDN.
Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.
“Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was,” he explained.
Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7–mm Hg reduction in 24-hour SBP “reasonably impressive – that’s actually a pretty good number for an antihypertensive clinical trial.” He was also favorably impressed by RDN’s safety in a 44-site study.
“The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications,” commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.
Simultaneous with Dr. Boehm’s presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).
The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.
SOURCE: Boehm M. ACC 2020, Abstract 406-15.
Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We saw clinically meaningful blood pressure reductions at 3 months,” reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.
That’s encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.
The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.
The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls. Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7–mm Hg reduction in 24-hour DBP, compared with a 0.8–mm Hg decrease in controls.
Office SBP – the secondary endpoint – decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.
These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1-2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons. Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.
A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.
The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.
A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%-9% nonetheless tested positive at the second test.
That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: “I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it’s fascinating that some of the people that you asked not to take the medications were taking them.”
While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance. At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don’t need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn’t undergo RDN.
Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.
“Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was,” he explained.
Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7–mm Hg reduction in 24-hour SBP “reasonably impressive – that’s actually a pretty good number for an antihypertensive clinical trial.” He was also favorably impressed by RDN’s safety in a 44-site study.
“The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications,” commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.
Simultaneous with Dr. Boehm’s presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).
The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.
SOURCE: Boehm M. ACC 2020, Abstract 406-15.
REPORTING FROM ACC 20
Primordial cardiovascular prevention draws closer
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
REPORTING FROM ACC 20